Pharmaceutical composition and use

ABSTRACT

An injectable, flowable composition, kits that include the same, and methods of medical treatment of a mammal (e.g., human) that include the administration of the same are provided.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority of U.S. ProvisionalPatent Application Ser. No. 61/592,438, entitled “PHARMACEUTICALCOMPOSITION AND USE,” filed on Jan. 30, 2012, which application isincorporated by reference herein in its entirety.

BACKGROUND

Patients with low back pain and related discomforts (e.g., sciatica) areoften treated with steroid suspensions or solutions that are injectedinto the epidural space. Methylprednisolone and dexamethasone are twosteroids commonly used in this practice. Over 3 million epidural steroidinjections are given annually in the United States to treat low backpain. The steroids methylprednisolone, dexamethasone, and betamethasoneare not currently approved by the Food and Drug Agency (FDA) for thisuse, and the procedure is commonly requires fluoroscopy to guide theinjection into a targeted space. It is not uncommon for patients toreceive two or three injections over the period of several months, whichnot only increases the risk of medical complications, but can also becostly, inconvenient, and time-consuming.

SUMMARY

The present invention provides an injectable, flowable composition thatincludes: (a) microparticles that include an active pharmaceuticalingredient and a polymer, wherein the surface of the microparticles arehydrophilic; and (b) a hydrophilic, liquid carrier vehicle; wherein themicroparticles are substantially miscible to dispersible in the liquidcarrier vehicle.

The present invention also provides an injectable, flowable compositionthat includes: (a) microparticles that include an active pharmaceuticalingredient and a polymer, wherein the surface of the microparticles arehydrophobic; and (b) a hydrophobic, liquid carrier vehicle; wherein themicroparticles are substantially miscible to dispersible in the liquidcarrier vehicle.

The present invention also provides a kit that includes: (a) a firstpackage (e.g., vial) that include microparticles that include an activepharmaceutical ingredient and a polymer, wherein the surface of themicroparticles are hydrophilic; (b) a second package (e.g., vial)comprising a hydrophilic, liquid carrier vehicle; and (c) instructionsor printed indicia; wherein the microparticles are substantiallymiscible to dispersible in the liquid carrier vehicle.

The present invention also provides a kit that includes: (a) a firstpackage (e.g., vial) that include microparticles that include an activepharmaceutical ingredient and a polymer, wherein the surface of themicroparticles are hydrophobic; (b) a second package (e.g., vial)comprising a hydrophobic, liquid carrier vehicle; and (c) Instructionsor printed indicla; wherein the microparticles are substantiallymiscible to dispersible in the liquid carrier vehicle.

The present invention also provides a method that includes administeringto a mammal (e.g., human), via injection, an injectable, flowablecomposition described herein.

The present invention also provides a method for the treatment of amedical condition or disorder (e.g., back pain). The method includesinjecting the injectable, flowable composition into lipophilic tissue(e.g., epidural space). The composition includes: (a) microparticlesthat include an active pharmaceutical ingredient and a polymer, whereinthe surface of the microparticles are hydrophilic; and (b) ahydrophilic, liquid carrier vehicle. The microparticles aresubstantially miscible to dispersible in the liquid carrier vehicle.

The present invention also provides a method for the treatment of amedical condition or disorder (e.g., macular degeneration or diabeticmacular edema). The method includes injecting the injectable, flowablecomposition into lipophobic tissue (e.g., intravitreal space of an eye).The composition includes: (a) microparticles that include an activepharmaceutical ingredient and a polymer, wherein the surface of themicroparticles are hydrophobic; and (b) a hydrophobic, liquid carriervehicle. The microparticles are substantially miscible to dispersible inthe liquid carrier vehicle.

Advantages of the invention include the stabilization and localizationof pharmaceutical agents in a targeted injection area for prolongedrelease of a pharmacological agent. In such embodiments, the injectedvolume remains localized in tissue. Spreading is diminished and deliveryof the agent to the target site is increased, and active agent exposureto unintended locations is diminished.

Advantages of the invention include the reduction of the risk of infarctor other adverse side-effects when the delivery vehicle is an aqueoussolution, if the practitioner injects the pharmaceutical compositionoutside the targeted injection site, e.g., into a blood vessel. Forexample, the compositions described herein are relatively effective andsafe for accidental or intentional arterial administration. In specificembodiments, the microparticle surface properties (hydrophilic) avoidsagglomeration. In additional embodiments, the particle size is smallenough to pass through capillaries. In additional embodiments, thehydrophilic surface particle and/or release of anti-inflammatory agentreduces the occurrence of an inflammatory response typically encounteredwith small diameter sized particles.

Advantages of the invention include the reduction of cost andinconvenience to both the patient and health insurance agenciesassociated with repeated therapeutic injections into the same area.

Advantages of the invention include the reduction of damaging effects onthe liver and other bodily filters in processing excess pharmaceuticalagents that are removed from the targeted injection site when usingconventional injection techniques.

Advantages of the invention include the use of a microparticle/deliveryvehicle suspension that has a high degree of stability, thus providingthe capability to perform accurate dosing without placing impractical orinconvenient limits of the time between mixing and loading the deliverydevice on the practitioner. For example, the compositions herein inspecific embodiments include a stable suspension (decreased settling)upon reconstitution (addition of diluent to microparticles), which canlead to more accurate dosing.

Advantages of the invention include, in specific embodiments, theselection of a poorly water-soluble and highly potent active agent. Thiscan decrease the exposure of the active agent to excipients. This canalso facilitate long duration or sustained release of the active agent.

Advantages of the invention include, in specific embodiments, theselection dexamethasone (or dexamethasone acetate) as the active agent.This specific active agent does not reduce or dehydrate neural tissue toany significant or appreciable degree.

DETAILED DESCRIPTION

Reference will now be made in detail to certain claims of the invention,examples of which are illustrated herein. While the presently disclosedsubject matter will be described in conjunction with the enumeratedclaims, it will be understood that the invention as described by thedisclosed subject matter does not limit the claims. On the contrary, thedisclosed subject matter is intended to cover all alternatives,modifications, and equivalents, which may be included within the scopeof the invention as defined by the claims.

References in the specification to “one embodiment”, “specificembodiments”, “an example embodiment”, etc., indicate that theembodiment described may include a particular feature, structure, orcharacteristic, but every embodiment may not necessarily include thatparticular feature, structure, or characteristic. Moreover, such phrasesare not necessarily referring to the same embodiment. Further, when aparticular feature, structure, or characteristic is described inconnection with an embodiment, it is submitted that it is within theknowledge of one skilled in the art to affect such feature, structure,or characteristic in connection with other embodiments whether or notexplicitly described.

The presently disclosed subject matter relates to injectable, flowablecompositions, methods of manufacturing the same, kits that include thesame, and methods of medical treatment that include administering thesame.

Injectable, Flowable Composition

In specific embodiments, the injectable, flowable composition includes:(a) microparticles that include an active pharmaceutical ingredient anda polymer, wherein the surface of the microparticles are hydrophilic;and (b) a hydrophilic, liquid carrier vehicle; wherein themicroparticles are substantially miscible to dispersible in the liquidcarrier vehicle. In alternative specific embodiments, the injectable,flowable composition includes: (a) microparticles that include an activepharmaceutical ingredient and a polymer, wherein the surface of themicroparticles are hydrophobic; and (b) a hydrophobic, liquid carriervehicle; wherein the microparticles are substantially miscible todispersible in the liquid carrier vehicle.

The hydrophilic, liquid carrier vehicle can include substances that aresuitable and appropriate for use as a liquid vehicle carrier. Inspecific embodiments, the hydrophilic, liquid carrier vehicle caninclude water.

The hydrophobic, liquid carrier vehicle can include substances that aresuitable and appropriate for use as a liquid vehicle carrier. Forexample, the hydrophobic, liquid carrier vehicle can include at leastone of an oil derived from a plant, an oil derived from asilicone-containing oil, and amicrobial/biological/biotechnology/fermentation/metabolic activity.

The injectable, flowable composition can be formulated to provide adesired or requisite rate of release of the API. In specificembodiments, the injectable, flowable composition can be formulated toprovide a sustained release of API. In additional specific embodiments,the injectable, flowable composition can be formulated to provide animmediate release of API. In additional specific embodiments, theinjectable, flowable composition can be formulated to provide anextended release of API. In additional specific embodiments, theinjectable, flowable composition can be formulated to provide a modifiedrelease of API. In additional specific embodiments, the injectable,flowable composition can be formulated to provide a combination (ormixture or hybrid) release of API, described above.

The injectable, flowable composition can have any suitable andappropriate pH. In specific embodiments, the injectable, flowablecomposition can have a pH of less than about 8.5. In additional specificembodiments, the injectable, flowable composition can have a pH of about7.0 to about 8.5.

In specific embodiments, the injectable, flowable composition caninclude a buffer. The inclusion of a buffer can depend on the chemistryor environmental factors (pH, etc.) of the intended target physiology.See, e.g., U.S. application Ser. No. 13/143,884.

The injectable, flowable composition can have any suitable andappropriate volume. In specific embodiments, it may be desirable toemploy an injectable, flowable composition having a relatively lowvolume, for patient safety, compliance, and comfort purposes. As such,in specific embodiments, the injectable, flowable composition can have atotal volume of less than about 50 mL. In additional specificembodiments, the injectable, flowable composition can have a totalvolume of less than about 20 mL In additional specific embodiments, theinjectable, flowable composition can have a total volume of less thanabout 5 mL. In additional specific embodiments, the injectable, flowablecomposition can have a total volume of less than about 1 mL.

Microparticles

The present invention provides an injectable, flowable composition thatincludes microparticles and a liquid carrier vehicle. The microparticlesinclude an active pharmaceutical ingredient and a polymer. The surfaceof the microparticles are either hydrophilic or hydrophobic. Themicroparticles are substantially miscible to dispersible in the liquidcarrier vehicle.

The microparticles include an active pharmaceutical ingredient andpolymer. The core of the microparticles can include an API (e.g.,dexamethasone acetate), which has relatively poor water-solubility, andpolymer (e.g., poly-lactide-co-gylocide (PLGA)); and the surface of themicroparticle can be functionalized with a polymer (e.g.,PLGA-co-polyethylene-glycol block copolymer, wherein the PEG block isdistal to the surface of the microparticle). The surface of themicroparticle can also include a specified amount of API, the amount ofwhich may be optimized to control burst release of the drug. U.S. Pat.No. 7,758,778 describes methods for preparing microparticle formulationscontaining pharmaceutically active agents.

The surface of the microparticles can be selected or modified throughfunctionalization to serve at least two purposes: first, to be solubleor miscible in the delivery vehicle, and second, to be Insoluble orimmiscible in the targeted physiological injection site. In general,microparticles incorporating pharmaceutical or pharmacologicalagents—and surface modification of the particles—can be prepared bymethods known in the art. See, for example, U.S. patent application Ser.No. 10/066,393, filed Jan. 31, 2002, and U.S. Pat. No. 6,497,729. Othersuitable synthetic methods known in the art can be employed.

The selection and/or modification through functionalization of thesurface of the microparticles provides a stable, homogeneous injectionsolution or suspension (to include the delivery vehicle and themicroparticles), minimizes precipitation or settling of themicroparticles, improves performance when administering the injectionsolution, and allows a practitioner to reliably administer an effectivedose of the pharmacological agent. At the same time, the immiscibilitybetween the injection solution or suspension and the targetedphysiological injection site provides the capability for themicroparticles to agglomerate at the injection site as described herein.

As such, the microparticles can include surface moieties selected toprovide a desired miscibility or solubility for a given application asdescribed herein; i.e., the microparticles can have a desiredhydrophilicity, hydrophobicity, lipophilicity, lipophobicity, or otherdesired miscibility or solubility characteristic. In one embodiment, themicroparticles can include surface moieties selected to maximizemiscibility or solubility within an injection vehicle, while at the sametime minimizing miscibility or solubility within a targetedphysiological environment. Specifically, the microparticles will besubstantially miscible or dispersible in the carrier vehicle, whereinthe microparticles and the carrier vehicle will be substantiallyinsoluble or immiscible in the targeted anatomical injection site of thepatient.

In specific embodiments, the microparticle surface includes asubstantially polar, water-miscible, or water-soluble material. Inalternative specific embodiments, the microparticle surface includes asubstantially non-polar, water-immiscible, or water-insoluble material.

In specific embodiments, an aqueous-miscible (i.e., a hydrophilic)microparticle can be prepared by functionalizing the microparticlesurface with an amphiphilic block copolymer. The block copolymer caninclude a hydrophobic block and a hydrophilic block, where thehydrophilic block is distal to the microparticle surface (i.e., theblock copolymer is oriented with the hydrophilic block furthest from themicroparticle surface). See, e.g., U.S. Pat. No. 5,565,215, filed Mar.18, 1994.

In specific embodiments, an aqueous-miscible (i.e., a hydrophilic)microparticle can be prepared by coating a hydrophobic microparticlewith a hydrophilic surface moiety, such as a polysaccharide,hylaranounic acid, or poly(ethylene glycol) (PEG). See, e.g., U.S.application Ser. No. 13/143,884, filed Jan. 8, 2010. The process ofmicroparticle surface coating may be done by methods known in the art,including grafting or linking methods.

In specific embodiments, a water-immiscible microparticle (e.g., amicroparticle having a substantially hydrophobic surface) can beprepared by the incorporation of a homopolymer or copolymer containinghydrophobic blocks, for example poly(lactide), poly(glycolide),poly(caprolactone), poly(valerolactone), poly(hydroxybutyrate), andcopolymers thereof.

In general, and without wishing to be bound by theory, it is believedthat when a carrier vehicle (e.g., an aqueous phase) containingsuspended microparticles is injected into a biological environmenthaving substantially different hydrophilicity or hydrophobicity than thesuspension or solution itself, the carrier vehicle will form a separatephase with respect to the environment (similar to injecting oil intowater). Over time, the carrier vehicle will be absorbed by the body,while the microparticles will remain substantially localized at theinjection site. Eventually, the carrier vehicle will be substantiallyabsorbed by the body, leaving a localized, agglomerated concentration ofthe microparticles at or substantially near the injection area. As themicroparticles degrade over time, and through diffusion processes, thepharmacological agent(s) contained therein can be released into theimmediate anatomical surroundings, providing localized delivery of thetherapeutic agent.

As is described in the art, accidental injection of a pharmacologicalagent into an unintended anatomy can pose serious health risks for thepatient. Injection of particulate matter into an artery can result inblocking or obstruction of the artery, resulting in damage to tissuerelying on the blood supplied by the blocked artery. This isparticularly true for biodegradable microparticles having a sizedimension greater than about 10 microns, since the microparticles cannotpass easily through capillary beds. As such, in specific embodiments,the microparticles described herein will have a size of about 10 micronsor less.

In general, the pharmaceutical compositions and methods described hereincan reduce the likelihood of infarct if a practitioner accidentlyinjects the pharmaceutical composition into a vein or artery. Thisadvantage is provided by at least two features of the pharmaceuticalcomposition: first, in some embodiments, the pharmaceutical compositioncan include microparticles having an average size of about 10 microns(μm) or less. This size range is believed to allow microparticles thatare accidently introduced into a blood supply to pass through thecapillary bed without causing obstruction. See, e.g., U.S. patentapplication Ser. No. 09/758,988, filed Jan. 11, 2001. Second, inembodiments where the biodegradable microparticles are hydrophilic, orhave been surface-functionalized to be hydrophilic, they will besubstantially miscible or soluble with blood. Thus, the risk of spinalcord infarct resulting from accidental injection outside of the targetinjection area (i.e., the epidural space), or into arteries that passthrough the epidural space can be reduced.

The microparticles employed herein will have a suitable and appropriatedimension. For example, the microparticles can be oval, spherical,elliptical, tubular, etc.

In additional to the shape, the microparticles will have a suitablesize. For example, the microparticles can have a d₅₀ of less than about5 μm. Specifically, the microparticles can have a d₅₀ of about 2 μm toabout 5 μm. Additionally, the microparticles can have a d₉₀ of less thanabout 7 μm. Specifically, the microparticles can have a d₉₀ of less thanabout 5 μm.

In specific embodiments, the microparticles are biodegradable. Inadditional specific embodiments, the microparticles are bioerodible. Inadditional specific embodiments, the microparticles are biocompatable.

The microparticles can be present in any suitable and appropriateconcentration, in the injectable, flowable composition. In specificembodiments, the microparticles can be present in a concentration ofabout 1 mg/ml to about 500 mg/ml of the liquid carrier vehicle.

API

Any suitable active pharmaceutical ingredient (API) can be employedherein, provided the resulting injectable, flowable composition retainsits chemical and physical stability, as well as requisite biologicalactivity, over the extended periods of time associated with themanufacture, shipping and storage of the product. Suitable APIs aredisclosed, for example, in the Merck Index (14^(th) Ed.) and the USPDictionary (2011). The selection of specific (or class) of API willtypically depend, e.g., on the underlying disease or disorder to betreated.

One specific class of APIs that can be employed includesanti-inflammatory agents, for example, synthetic, glucocorticoldsteroids. Within the synthetic, glucocorticoid steroids, a specific APIthat can be employed is dexamethasone acetate, 9 alpha-fluoro-11-beta,17-alpha, 21-trihydroxy-16 alpha-methylpregna-1,4-diene-3,20-dione21-acetate.

Use of dexamethasone acetate as an anti-inflammatory agent can beadvantageous in specific embodiments. Dexamethasone acetate has arelatively low water-solubility, which facilitates sustained drugdelivery from the biodegradable microparticles. Additionally, the drughas been shown to be a relatively potent corticosteroid that does notreduce water content of neural tissue.

Dexamethasone acetate has higher anti-inflammatory potency than manyother corticosteroids, which may reduce the number of doses needed totreat the patient. Dexamethasone acetate also has low water solubility,<0.15 mg/mL, which can be preferred for formulation of asustained-release dosage form. As diffusion and polymer degradation aretwo main mechanisms of drug release from biodegradable microparticles, apharmacological agent having lower water solubility may elute at aslower rate from the microparticles compared to other agents with highwater solubility. Furthermore, dexamethasone acetate has been shown toachieve an anti-inflammatory effect in the brain without reducing tissuewater content. See, e.g., H. James, “Effects of Steroids on Behavior,Electrophysiology, Water Content and Intracranial Pressure in CerebralCytotoxic Edema,” Pharmacology Biochemistry and Behavior, Vol. 9, pp.653-657, 1978. Thus, in specific embodiments, it can be advantageous tochoose dexamethasone acetate for treatment of low back pain to avoidreduction in water content of the targeted nerve roots.

Selection of the API will depend in part upon the underlying disease ordisorder to be treated. For example, the composition described herein,including the API, can be administered via an intravitreal injectioninto the eye. For such an administration, the composition can beemployed to treat, e.g., macular degeneration or diabetic macular edema.APIs suitable for the treatment of such diseases or disorders aredisclosed, e.g., in the Merck Index (14^(th) Ed.) and the USP Dictionary(2011). For example, in embodiments where the composition is employed totreat diabetic macular edema, via an intravitreal injection into theeye, the API can include dexamethasone acetate.

The API can be present in the injectable, flowable composition in anysuitable and appropriate amount. For example, the API can be present inthe injectable, flowable composition in an amount such that theresulting injectable, flowable composition retains its chemical andphysical stability, as well as requisite biological activity, over theextended periods of time associated with the manufacture, shipping andstorage of the product.

In specific embodiments, it may be desirable to maximize, or increase,the amount of API present, relative to the total amount of injectable,flowable composition. In such embodiments, it may be desirable to employan injectable, flowable composition having a relatively low volume, forpatient safety, compliance, and comfort purposes.

As such, in specific embodiments, the active pharmaceutical ingredientcan be present in a weight of up to about 40% the weight of the polymer.In further specific embodiments, the active pharmaceutical Ingredientcan be present in a weight of up to about 30% the weight of the polymer.In alternative specific embodiments, the active pharmaceuticalingredient can be present in a weight of at least about 10% the weightof the polymer. In further specific embodiments, the activepharmaceutical ingredient can be present in a weight of at least about20% the weight of the polymer. In alternative specific embodiments, theactive pharmaceutical Ingredient can be present in a weight of about20-30% the weight of the polymer.

The specific amount (measured in units of mass) of API employed in theinjectable, flowable composition will typically depend, for example, onthe amount of composition to be delivered. The amount of composition tobe delivered will typically depend, for example, on the size, weight,age and health condition of the patient, the disease or disorder to betreated, the location or site of administration, as well as the specificAPI employed.

Polymer

In specific embodiments, the polymer can include an amphiphilic blockcopolymer. In additional specific embodiments, the polymer can include acopolymer of lactic acid and glycolic acid (e.g., PLGA). In additionalspecific embodiments, the polymer can include at least one ofPLGA-block-PEG and PLGA.

In specific embodiments, the surface of the microparticles can behydrophilic. In such embodiments, the liquid carrier vehicle can behydrophilic, and the polymer can include a PLGA core and aPLGA-block-PEG surface. Additionally, in specific embodiments whereinthe surface of the microparticles are hydrophilic and the liquid carriervehicle is hydrophilic, the resulting injectable, flowable compositioncan be configured for injection into a hydrophobic environment (e.g.,fatty tissue, an epidural space, etc.).

Alternatively, in specific embodiments, the surface of themicroparticles can be hydrophobic. In such embodiments, the liquidcarrier vehicle can be hydrophobic, and the polymer can include PLGA.Additionally, in specific embodiments wherein the surface of themicroparticles are hydrophobic, and the liquid carrier vehicle ishydrophobic, then the injectable, flowable composition can be configuredfor injection into a hydrophilic environment (e.g., an eye, orsurrounding tissue, the vitreous body of an eye, or surrounding tissue,a joint, the synovial cavity of a joint, etc.).

In specific embodiments, the PLGA can be poly(D,L-lactide-co-glycolide).In additional specific embodiments, PLGA can bepoly(D,L-lactide-co-glycolide) [50:50 to 95:5].

In specific embodiments, the PLGA-block-PEG surface can bepoly(D,L-lactide-co-glycolide)-co-polyethylene glycol. In additionalspecific embodiments, the PLGA-block-PEG surface can bepoly(D,L-lactide-co-glycolide) [50:50 to 95:5]-co-polyethylene glycol.In additional specific embodiments, the PLGA-block-PEG surface can bepoly(D,L-lactide-co-glycolide)[85:15]-co-polyethylene glycol.

The PEG portion of the PLGA-block-PEG polymer can have a suitable andappropriate molecular weight range. For example, in specificembodiments, the PEG portion of the PLGA-block-PEG polymer can have amolecular weight of up to 10,000 daltons. In additional specificembodiments, the PEG portion of the PLGA-block-PEG polymer can have amolecular weight of about 2 kD.

Kits

The kit can include all of the desired tools, solutions, compounds,including mixing vessels, utensils, and injection devices, to treat apatient according to any of the methods described herein. In oneembodiment, a kit includes pharmaceutically-active biodegradablemicroparticles of the type described herein. The microparticles can besterile-packaged as a dry powder in a substantially water-impermeablecontainer. The kit can also include an injection vehicle such as sterilewater (in the case where the target injection area is substantiallyhydrophobic or lipophilic) or other suitable vehicle. Prior toadministration, the biodegradable microparticles can be added to theinjection vehicle to form a suspension and agitated (e.g., stirred orshaken) to maximize homogeneity. The kit can further include ahypodermic needle or other delivery device. The kit can further includeinstructions, dosage tables, and other pertinent information for thepractitioner.

The kits will include instructions or printed indicia, to provide fordirections for reconstituting the contents of the multiple packages,and/or for the administration of the resulting composition (e.g., theinjectable, flowable composition). In specific embodiments, theinstructions on printed indicia will instruct injection into at leastone of fatty tissue, hydrophobic tissue, and epidural tissue. Inadditional specific embodiments, the instructions on printed indiciawill instruct injection into at least one of hydrophilic tissues, aneye, and vitreous.

Methods for Use (Medical Treatment)

The microparticles described herein can be stored, e.g., as alyophilized powder in a sealed, dry container. Prior to injection, theparticles can be mixed with an injection vehicle, and an aliquot of theresulting suspension can be collected for injection into the patient. Intypical settings, this procedure can be done by drawing the suspensioninto a hypodermic needle for subcutaneous injection. However, othermethods of delivering the suspension to a desired injection are can beused. In one embodiment, a 22 gauge, 3.5 inch Quincke spinal needle canbe used. In another embodiment, a Touhy needle can be used. Othermethods will be apparent to those skilled in the art. See, e.g., Cohenet al, “Randomized, Double-blind, Placebo-controlled, Dose Response, andPreclinical Safety Study of Transforaminal Epidural Etanercept for thetreatment of Sciatica,” Anesthesiology, Vol. 110, pp. 1116-1126 (2009).

One problem with existing microparticle formulations is settling of themicroparticles in the delivery vehicle, which can affect patient dosing.A uniform, but unstable suspension of biodegradable microparticles canbe achieved, in prior art systems and methods, by mixing or stirring themicroparticles into the delivery vehicle. It then becomes necessary, inmost cases, to immediately load the suspension into the delivery device(e.g. a hypodermic needle) immediately after mixing since themicroparticles will begin to settle after a period of time. Theconcentration of microparticles in the suspension can vary using thistype of approach, since the amount of time between mixing, needleloading, and injection depend on the practitioner-dependent variables.

In contrast, advantages of the invention include the use of amicroparticle/delivery vehicle suspension that has a high degree ofstability, thus providing the capability to perform accurate dosingwithout placing impractical or inconvenient limits of the time betweenmixing and loading the delivery device on the practitioner.

The injectable, flowable compositions described herein can be formulatedfor administration, via injection, to a mammal (e.g., human).

As described herein, the injectable, flowable composition can beformulated to provide a desired or requisite rate of release of the API.In specific embodiments, the injectable, flowable composition can have asubstantially first order release profile. In alternative specificembodiments, the injectable, flowable composition can have asubstantially zero order release profile.

As stated herein, in specific embodiments, the surface of themicroparticles can be hydrophilic. In such embodiments, the liquidcarrier vehicle can be hydrophilic, and the polymer can include a PLGAcore and a PLGA-block-PEG surface. Additionally, in specific embodimentswherein the surface of the microparticles are hydrophilic and the liquidcarrier vehicle is hydrophilic, the resulting injectable, flowablecomposition can be injected into a hydrophobic environment (e.g., fattytissue, an epidural space, etc.). A non-limiting example of a lipophilicregion of a patient anatomy includes the epidural space. See, e.g.,Rathmell, J. P. et al., “Identification of the Epidural Space withOptical Spectroscopy,” Anesthesiology, Vol. 113(6), December, 2010, pp1406-1418; and Hogan, Q. H., “Lumbar Epidural Anatomy,” Anesthesiology,Vol. 75(5), November 1991, pp. 767-775.

As stated herein, in alternative specific embodiments, the surface ofthe microparticles can be hydrophobic. In such embodiments, the liquidcarrier vehicle can be hydrophobic, and the polymer can include PLGA.Additionally, in specific embodiments wherein the surface of themicroparticles are hydrophobic, and the liquid carrier vehicle ishydrophobic, then the injectable, flowable composition can be injectedinto a hydrophilic environment (e.g., an eye, or surrounding tissue, thevitreous body of an eye, or surrounding tissue, a joint, the synovialcavity of a joint, etc.).

As stated herein, the selection of specific (or class) of API willtypically depend, e.g., on the underlying disease or disorder to betreated. In specific embodiments where the API is an anti-inflammatoryagent, for example, a synthetic, glucocorticoid steroid, such asdexamethasone acetate, the disease or disorder to be treated can includeat least one of: pain, chronic pain, mild pain, moderate pain, severepain, acute pain, neuropathic pain, lower back pain, sciatica,radiculopathy, and lumbrosacral radiculopathy.

As stated herein, the flowable composition can be injected into ahydrophilic environment (e.g., an eye, or surrounding tissue, thevitreous body of an eye, or surrounding tissue, a joint, the synovialcavity of a joint, etc.), or can be injected into a hydrophobicenvironment (e.g., fatty tissue, an epidural space, etc.). As such, theinjection can include intradermal as well as subcutaneous injections.

Depending upon the selection of polymer, microparticle, API, etc., theAPI can be released into the target injection site area over a specifiedperiod of time. For example, the polymer, microparticle, and API canindependently be selected for release of the API into the targetinjection area over a period of days, weeks, or months. This process canoccur by, e.g., diffusion of the API out of the microparticles; or bythe microparticles dissolving or decomposing over time, which canrelease the API into the injection site. In one embodiment, themicroparticles are capable of releasing the API over selectable periodsranging from about 2-24 weeks. Thus, a patient can receivesubstantially-continual dosing of the API over extended periods, ifdesired, which can reduce the need to receive repeated injectiontreatments.

The injectable, flowable compositions described herein can be formulatedfor administration, via injection, to a mammal (e.g., human), over asuitable, appropriate and effective period of time. In specificembodiments, the administration can be carried out no more than once perabout 2 weeks. In additional specific embodiments, the administrationcan be carried out no more than once per about 6 weeks. In additionalspecific embodiments, the administration can be carried out no more thanonce per about 12 weeks. In additional specific embodiments, theadministration can be carried out no more than once per about 18 weeks.In additional specific embodiments, the administration can be carriedout no more than once per about 24 weeks.

In specific embodiments, the administration is carried out withfluoroscopy. In alternative specific embodiments, the administration iscarried out without fluoroscopy.

Enumerated Embodiments

Specific enumerated embodiments [1] to [82] provided below are forillustration purposes only, and do not otherwise limit the scope of thedisclosed subject matter, as defined by the claims. These enumeratedembodiments encompass all combinations, sub-combinations, and multiplyreferenced (e.g., multiply dependent) combinations described therein.

[1.] An injectable, flowable composition comprising:

(a) microparticles comprising an active pharmaceutical ingredient and apolymer, wherein the surface of the microparticles are hydrophilic; and

(b) a hydrophilic, liquid carrier vehicle;

wherein the microparticles are substantially miscible to dispersible inthe liquid carrier vehicle.[2.] An injectable, flowable composition comprising:

(a) microparticles comprising an active pharmaceutical ingredient and apolymer, wherein the surface of the microparticles are hydrophobic; and

(b) a hydrophobic, liquid carrier vehicle;

wherein the microparticles are substantially miscible to dispersible inthe liquid carrier vehicle.[3.] The injectable, flowable composition of any of the aboveembodiments, wherein the microparticles have a d₅₀ of less than about 5μm.[4.] The injectable, flowable composition of any of the aboveembodiments, wherein the microparticles have a d₅₀ of about 2 μm toabout 5 μm.[5.] The injectable, flowable composition of any of the aboveembodiments, wherein the microparticles have a d₉₀ of less than about 7μm.[6.] The injectable, flowable composition of any of the aboveembodiments, wherein the microparticles have a d₉₀ of less than about 5μm.[7.] The injectable, flowable composition of any of the aboveembodiments, wherein the active pharmaceutical ingredient comprises ananti-inflammatory agent.[8.] The injectable, flowable composition of any of the aboveembodiments, wherein the active pharmaceutical ingredient comprises asynthetic, glucocorticoid steroid.[9.] The injectable, flowable composition of any of the aboveembodiments, wherein the active pharmaceutical ingredient comprisesdexamethasone acetate, 9 alpha-fluoro-11-beta, 17-alpha,21-trihydroxy-16 alpha-methylpregna-1,4-diene-3,20-dione 21-acetate

[10.] The injectable, flowable composition of any of the aboveembodiments, wherein the polymer comprises an amphiphilic blockcopolymer.[11.] The injectable, flowable composition of any of the aboveembodiments, wherein the polymer is a copolymer of lactic acid andglycolic acid (PLGA).[12.] The injectable, flowable composition of any of the aboveembodiments, wherein the polymer is a random or block copolymer oflactic acid and glycolic acid (PLGA).[13.] The injectable, flowable composition of any of the aboveembodiments, wherein the polymer comprises at least one ofPLGA-block-PEG and PLGA.[14.] The injectable, flowable composition of any of the aboveembodiments, wherein when (i) the surface of the microparticles arehydrophilic, and (ii) the liquid carrier vehicle is hydrophilic, thenthe polymer comprises a PLGA core and a PLGA-block-PEG surface.[15.] The injectable, flowable composition of any of the aboveembodiments, wherein when (i) the surface of the microparticles arehydrophobic, and (ii) the liquid carrier vehicle is hydrophobic, thenthe polymer comprises PLGA.[16.] The injectable, flowable composition of any of the aboveembodiments, wherein the PLGA is poly(D,L-lactide-co-glycolide)[50:50 to95:5].[17.] The injectable, flowable composition of any of the aboveembodiments, wherein the PLGA-block-PEG surface ispoly(D,L-lactide-co-glycolide)[50:50 to 95:5]-co-polyethylene glycol.[18.] The injectable, flowable composition of any of the aboveembodiments, wherein the PLGA-block-PEG surface ispoly(D,L-lactide-co-glycolide)[85:15]-co-polyethylene glycol.[19.] The injectable, flowable composition of any of the aboveembodiments, wherein the PEG portion of the PLGA-block-PEG polymer has amolecular weight of up to 10,000 daltons.[20.] The injectable, flowable composition of any of the aboveembodiments, wherein the PEG portion of the PLGA-block-PEG polymer has amolecular weight of about 2 kD.[21.] The injectable, flowable composition of any of the aboveembodiments, wherein the microparticles are biodegradable.[22.] The injectable, flowable composition of any of the aboveembodiments, wherein the microparticles are bioerodible.[23.] The injectable, flowable composition of any of the aboveembodiments, wherein the microparticles are biocompatible.[24.] The injectable, flowable composition of any of the aboveembodiments, wherein the active pharmaceutical ingredient is present ina weight of up to about 40% the weight of the polymer.[25.] The injectable, flowable composition of any of the aboveembodiments, wherein the active pharmaceutical ingredient is present ina weight of up to about 30% the weight of the polymer.[26.] The injectable, flowable composition of any of the aboveembodiments, wherein the active pharmaceutical ingredient is present ina weight of at least about 10% the weight of the polymer.[27.] The injectable, flowable composition of any of the aboveembodiments, wherein the active pharmaceutical ingredient is present ina weight of at least about 20% the weight of the polymer.[28.] The injectable, flowable composition of any of the aboveembodiments, wherein the active pharmaceutical ingredient is present ina weight of about 20-30% the weight of the polymer.[29.] The injectable, flowable composition of any of the aboveembodiments, wherein when (i) the surface of the microparticles arehydrophilic, and (ii) the liquid carrier vehicle is hydrophilic, thenthe injectable, flowable composition is configured for injection into ahydrophobic environment.[30.] The Injectable, flowable composition of any of the aboveembodiments, wherein when (i) the surface of the microparticles arehydrophilic, and (ii) the liquid carrier vehicle is hydrophilic, thenthe injectable, flowable composition is configured for injection intofatty tissue.[31.] The injectable, flowable composition of any of the aboveembodiments, wherein when (i) the surface of the microparticles arehydrophilic, and (ii) the liquid carrier vehicle is hydrophilic, thenthe injectable, flowable composition is configured for injection into anepidural space.[32.] The injectable, flowable composition of any of the aboveembodiments, wherein when (i) the surface of the microparticles arehydrophobic, and (ii) the liquid carrier vehicle is hydrophobic, thenthe injectable, flowable composition is configured for injection into ahydrophilic environment.[33.] The injectable, flowable composition of any of the aboveembodiments, wherein when (i) the surface of the microparticles arehydrophobic, and (ii) the liquid carrier vehicle is hydrophobic, thenthe injectable, flowable composition is configured for injection into aneye, or surrounding tissue.[34.] The injectable, flowable composition of any of the aboveembodiments, wherein when (i) the surface of the microparticles arehydrophobic, and (ii) the liquid carrier vehicle is hydrophobic, thenthe injectable, flowable composition is configured for injection intothe vitreous fluid of an eye.[35.] The injectable, flowable composition of any of the aboveembodiments, wherein when (i) the surface of the microparticles arehydrophobic, and (ii) the liquid carrier vehicle is hydrophobic, thenthe injectable, flowable composition is configured for injection intothe synovial cavity of a joint.[36.] The injectable, flowable composition of any of the aboveembodiments, wherein the hydrophilic, liquid carrier vehicle comprisesan aqueous liquid.[37.] The injectable, flowable composition of any of the aboveembodiments, wherein the hydrophilic, liquid carrier vehicle compriseswater.[38.] The injectable, flowable composition of any of the aboveembodiments, wherein the hydrophobic, liquid carrier vehicle comprisesat least one of an oil derived from a plant, an oil derived from amicrobial/biological/biotechnology/fermentation/metabolic activity, anda silicone-containing oil.[39.] The injectable, flowable composition of any of the aboveembodiments, which is a sustained release composition.[40.] The injectable, flowable composition of any of the aboveembodiments, which is a controlled release composition.[41.] The injectable, flowable composition of any of the aboveembodiments, which is a modified release composition.[42.] The injectable, flowable composition of any of the aboveembodiments, wherein the microparticles are present in a concentrationof about 1 mg/ml to about 500 mg/ml of the liquid carrier vehicle.[43.] The injectable, flowable composition of any of the aboveembodiments, wherein the microparticles were previously lyophilized.[44.] The injectable, flowable composition of any of the aboveembodiments, having a pH of less than about 8.5.[45.] The injectable, flowable composition of any of the aboveembodiments, having a pH of about 7.0 to about 8.5.[46.] The injectable, flowable composition of any of the aboveembodiments, having a total volume of less than about 20 ml, or lessthan about 5 mL.[47.]A kit comprising:

-   -   a first package comprising microparticles comprising an active        pharmaceutical ingredient and a polymer, wherein the surface of        the microparticles are hydrophilic;    -   a second vial comprising a hydrophilic, liquid carrier vehicle;        and    -   instructions or printed indicia;        wherein the microparticles are substantially miscible to        dispersible in the liquid carrier vehicle.        [48.]A kit comprising:    -   a first vial comprising microparticles comprising an active        pharmaceutical ingredient and a polymer, wherein the surface of        the microparticles are hydrophobic;    -   a second vial comprising a hydrophobic, liquid carrier vehicle;        and    -   instructions or printed indicia;        wherein the microparticles are substantially miscible to        dispersible in the liquid carrier vehicle.        [49.] The kit of any of the above embodiments, wherein the        instructions or printed indicia provide for a directions for        reconstituting, which include contacting the contents of the        first vial with the contents of the second vial, thereby        providing a reconstituted composition that is injectable and        flowable.        [50.] The kit of any of the above embodiments, wherein the        microparticles were previously lyophilized.        [51.] The kit of any of the above embodiments, wherein the        instructions on printed indicia instruct injection into at least        one of fatty tissue, hydrophobic tissue, and epidural tissue.        [52.] The kit of any of the above embodiments, wherein the        instructions on printed indicia instruct injection into at least        one of hydrophilic tissues, an eye, vitreous fluid, a joint, and        the synovial cavity of a joint.        [53.] The kit of any of the above embodiments, further        comprising a hypodermic needle or other delivery device.        [54.] A method comprising administering to a mammal (e.g.,        human), via injection, the injectable, flowable composition of        any of the above embodiments.        [55.] The method of any of the above embodiments, wherein the        injectable, flowable composition has a substantially first order        release profile.        [56.] The method of any of the above embodiments, wherein the        injectable, flowable composition has a substantially zero order        release profile.        [57.] The method of any of the above embodiments, wherein        when (i) the surface of the microparticles are hydrophilic,        and (ii) the liquid carrier vehicle is hydrophilic, then the        injectable, flowable composition is injected into a hydrophobic        environment.        [58.] The method of any of the above embodiments, wherein        when (i) the surface of the microparticles are hydrophilic,        and (ii) the liquid carrier vehicle is hydrophilic, then the        injectable, flowable composition is injected into fatty tissue.        [59.] The method of any of the above embodiments, wherein        when (i) the surface of the microparticles are hydrophilic,        and (ii) the liquid carrier vehicle is hydrophilic, then the        injectable, flowable composition is injected into an epidural        space.        [60.] The method of any of the above embodiments, wherein        when (i) the surface of the microparticles are hydrophobic,        and (ii) the liquid carrier vehicle is hydrophobic, then the        injectable, flowable composition is injected into a hydrophilic        environment.        [61.] The method of any of the above embodiments, wherein        when (I) the surface of the microparticles are hydrophobic,        and (ii) the liquid carrier vehicle is hydrophobic, then the        injectable, flowable composition is injected into an eye, or        surrounding tissue.        [62.] The method of any of the above embodiments, wherein        when (i) the surface of the microparticles are hydrophobic,        and (ii) the liquid carrier vehicle is hydrophobic, then the        injectable, flowable composition is injected, via an        intravitreal injection, into the eye.        [63.] The method of any of the above embodiments, wherein        when (i) the surface of the microparticles are hydrophobic,        and (ii) the liquid carrier vehicle is hydrophobic, then the        injectable, flowable composition is injected into a joint.        [63.] The method of any of the above embodiments, wherein        when (i) the surface of the microparticles are hydrophobic,        and (ii) the liquid carrier vehicle is hydrophobic, then the        injectable, flowable composition is injected into the synovial        cavity of a joint.        [65.] The method of any of the above embodiments, for the        treatment of pain.        [66.] The method of any of the above embodiments, for the        treatment of chronic pain.        [67.] The method of any of the above embodiments, for the        treatment of mild pain.        [68.] The method of any of the above embodiments, for the        treatment of moderate pain.        [69.] The method of any of the above embodiments, for the        treatment of severe pain.        [70.] The method of any of the above embodiments, for the        treatment of acute pain.        [71.] The method of any of the above embodiments, for the        treatment of neuropathic pain.        [72.] The method of any of the above embodiments, for the        treatment of lower back pain.        [73.] The method of any of the above embodiments, for the        treatment of sciatica.        [74.] The method of any of the above embodiments, for the        treatment of radiculopathy.        [75.] The method of any of the above embodiments, for the        treatment of lumbrosacral radiculopathy.        [76.] The method of any one of the above embodiments, wherein        the administration is not intradermal or subcutaneous.        [77.] The method of any one of the above embodiments, wherein        the administration is epidural.        [78.] The method of any one of the above embodiments [60]-[62],        wherein the administration is carried out for the treatment of        macular degeneration, or for the treatment of diabetic macular        edema.        [79.] The method of any one of the above embodiments, wherein        the administration is carried out no more than once per about 12        weeks.        [80.] The method of any one of the above embodiments, wherein        the administration is carried out no more than once per about 24        weeks.        [81.] The method of any one of the above embodiments, wherein        the administration is carried out with fluoroscopy.        [82.] The method of any one of the above embodiments, wherein        the administration is carried out without fluoroscopy.

EXAMPLES

The following illustrative examples are provided to facilitate testing,determine effective dosing, and describe preferred methods for use ofthe pharmaceutical compositions described herein. The examples below arenon-limiting with respect to the claims.

Materials and Methods

To facilitate accurate dosing, the amount of API present in a sample ofbiodegradable microparticles can be determined. In one approach, asample of microparticles of the type described herein can be dissolvedin an appropriate solvent to form a mixture; the mixture can then beanalyzed by known analytical techniques, such as high-performance liquidchromatography (HPLC) and comparing results to those of known referencestandards. Other analytical techniques can be used, e.g., spectroscopicanalysis.

In-vitro elution of the API from the microparticles can be determined byadding a known amount of the microparticles to 5 mL phosphate bufferedsaline (PBS) solution at a pH 7.4, and maintaining a constanttemperature of 37° C. At selected time intervals, a 2 mL aliquot can bewithdrawn through a 0.4 μm filter for analysis; the amount of thealiquot withdrawn can be replenished with an equal amount of preheatedPBS. The concentration of the API in the aliquot can be determinedaccording to known methods such as HPLC. Sampling intervals can beadjusted to maintain drug concentration below sink conditions in thetest vials.

In one approach, particle size distribution of the various microparticleformulations can be determined by laser diffraction and characterized byscanning electron microscopy. The stability of a suspension ofmicroparticles within a carrier vehicle can be determined by observingsettling times. These data can be confirmed by assaying aliquots fromtop, middle, and bottom locations of the suspension at selected timeintervals, e.g., 1 hour, 5 hours, 24 hours, etc.

Synthesis of Microparticles and Testing of Dosage Forms

Procedure [A1]: Microparticle having a Hydrophilic Surface Created byBlock Copolymer—Aqueous Vehicle

In this example, microparticles containing an active API can be preparedusing the following oil in water emulsion technique. First, an oil phasecan be prepared by dissolving dexamethasone acetate and PEG-block-PLGA(mPEG 5000 initiated PLGA with 75/25 lactic acid/glycolic acid molarratio) in dichloromethane. A water phase can be prepared by dissolvinghydrolyzed polyvinyl alcohol (PVA) in deionized water. The deionizedwater can be saturated with dichloromethane and dexamethasone acetate.Next, the oil phase can be added to the water phase and an emulsion canbe formed by agitating with a high-shear rotary immersion mixer. Theresulting oil-in-water emulsion can be further processed through ahigh-shear microfluidizer to reduce the oil droplet size, then stirredto allow the PEG chains to orientate to the oil droplet surface. Theresulting emulsion can be added to an excess of deionized water andcontinuously agitated to harden the polymeric microparticles. Next,after about 60 minutes, the resulting microparticles can beprogressively isolated through 50 μm, 10 μm, and 1 μm filters. Theparticles collected on the 1 micron filter can be washed with deionizedwater, lyophilized, and stored in sealed containers under refrigerationfor further analysis. Sealed vials can be gamma-irradiated prior toanalysis or administration.

Procedure [A2]: Microparticle Having a Hydrophilic Surface Created byBlock Copolymer—Aqueous Vehicle

One alternative approach includes the steps above of Procedure A1, butadditional PLGA is added to the oil phase with the dexaemethasoneacetate and PEG-block-PLGA. This reduces the overall PEG content of theresulting microparticle.

Procedure [A3]: Microparticle having a Hydrophilic Surface Created byBlock Copolymer—Aqueous Vehicle

One alternative approach includes the steps above of Procedure A1, butthe emulsion is not microfluidized, and the hardened microparticles canbe progressively isolated through 100 μm and 20 μm filters.

Without wishing to be bound by theory, it is believed that the blockcopolymer PEG-co-PLGA may associate with several surfaces or interfaces:a) the surface of the oil phase droplets in the emulsion acting as asurfactant; b) the hydrophobic blocks with the oil phase; and c) thehydrophilic PEG blocks with the surrounding water phase. Upon hardening,the surface of the microparticles may include PEG-co-PLGA on thesurface.

Microparticles prepared according to Procedure [A1] above can bepredicted to have an average diameter of about 5 μm and a maximumdiameter of about 9 μm. Microparticles prepared according to procedureA3 above can be predicted to have an average diameter of about 40 μm anda maximum diameter of about 100 μm.

In general, without wishing to be bound by theory, the percent-by-weight(% weight) of active API contained within microparticles prepared by theabove methods can be approximately equal to, or slightly less than the %weight of the agent with respect to the oil-phase polymer. In the aboveexamples, dexamethasone acetate can be estimated to be 25% by weight ofthe microparticle. It will be understood that the amount of APIcontained in the microparticle can be adjusted by varying the drug topolymer ratio in the oil phase. In addition, the API may be incorporatedinto the oil phase as a suspension if a solvent is used that solubilizesthe polymer, but not the agent.

Microparticles prepared according to the above steps can be expected toform a stable suspension in water over a reasonable range of solidcontent, e.g., 1-30% solid content. Such suspension can be stable forgreater than 2 hours, which is typically long enough to enable aphysician or other practitioner to form and administer the suspensioninto a patient.

Without wishing to be bound by theory, it can be reasonably expectedthat dexamethasone acetate will release continuously over 12 weeksin-vitro, with about 10% of the drug released in 3 days, 25% in 25 days,and 40% in 70 days. It will be understood that the release profile maybe adjusted by one or more of the following, including combinations:increasing or decreasing drug to polymer ratio; increasing or decreasingpolymer molecular weight; increasing or decreasing particle size;increasing or decreasing polymer degradation time (by decreasing orincreasing glycolic acid content); or increasing or decreasinghydrophilicity of microparticle surface.

In-Vivo Studies Epidural Administration in Canine Subjects UsingFluoroscopically-Guided Injection

This exemplary approach is a modified version of that described by Cohen(vide supra). Male and female beagles can be acclimated and subjected tobaseline neurologic and clinical chemistry examinations. Prior totreatment dogs can be anesthetized with propofol. The injection site canbe shaved, and a 19-gauge epidural Touhy needle can be inserted at theL6-7 or L7-S1 interspace. A 22-gauge catheter can be threaded 8-10 cm toapproximately the L2-L3 level. The position of the catheter can beverified by injection of contrast media under fluoroscopy. Two (2) mL ofan aqueous suspension of microparticles, prepared according to procedureA1 above, can be injected over a period of about 2 minutes. After about10 minutes the catheter can be removed. Before and after surgery,subject baseline measurements can be obtained, including, for example,temperature and specific behavioral measures (pain tolerance, reflex,mobility, etc.). Before injection, and every 2 days after injection for84 days, heart rate, blood pressure in the tail, spinal reflexes,sensory and pain responses, proprioception, gait and movement, cranialnerve function, and fundoscopic examination data can be recorded toobserve the safety of the injected pharmaceutical composition. Bloodsamples can be collected prior to injection, then at 1, 2, 4, 8, 24, and72 hour intervals after injection, and every 7 days thereafter toanalyze for the pharmaceutical agent and its metabolized forms. Atscheduled intervals, necropsy and histopathology can be performed asdescribed by Cohen, vide supra, in a sub-set of animals.

Without wishing to be bound by theory, pharmaceutical compositions ofthe type described herein are not expected to elicit any significant orappreciable degree of inflammatory response or cause necrosis.Histological examination may reveal the microparticles to be localizedand agglomerated within the epidural space at the site of injection withno evidence of the presence of the injection vehicle after 2 about days.Contents of the treated epidural pocket can be recovered by dissection.The injected microparticles can be isolated from epidural tissue andassayed for drug concentration to determine an in-vivo elution profile.It can be reasonably expected that dexamethasone acetate will bereleased continuously over 12 weeks, with about 20% of the drug releasedin 3 days, 50% in 25 days, and 80% in 70 days, with completemicroparticle polymer degradation in about 16 weeks.

As described above, pharmaceutical compositions of the type describedherein can be used to reduce the risk of medical complications stemmingfrom infarct. Canines can be prepared for treatment as described above.A targeted injection location for the microparticles can be verifiedwith contrast media prior to administration. Three dogs can be given a 2mL injection of a pharmaceutical composition prepared by procedure A1above, directly into an artery that passes through the epidural spaceand 3 dogs can be given an injection of a pharmaceutical composition ofthe type described herein where the microparticles have an average sizelarger than 10 μm. For example, a pharmaceutical composition prepared byprocedure A3, above, can be used. Before and every 2 hours after eachinjection, heart rate, blood pressure in the tail, spinal reflexes,sensory and pain responses, proprioception, gait and movement, andcranial nerve function, can be measured. After 24 hours,necropsy/histopathology can be performed as described above to determinethe degree of infarct, if any, present in subjects injected with thelarger microparticle composition.

It can be reasonably expected that animals injected with microparticleshaving an average size of less than 10 μm will not show a difference inbehavior or vitality over the 24 hour period, nor will their vital signschange drastically. Histological examination of the injected and distalarteries is not expected to reveal evidence of thrombus formation,vessel inflammation, or clotting. In contrast, animals injected with thelarger microparticle composition may exhibit signs of paralysis.Histological examination of the injected and distal arteries may revealsevere clotting in distal arteries that supply blood to the spinal cord.

Formula [B]: Microparticles Having a Hydrophobic Surface—Oil BasedVehicle

Microparticles can be prepared by the oil in water emulsion technique.An oil phase can be prepared by dissolving dexamethasone acetate and75/25 poly-lactic-co-glycolic acid in dichloromethane. A water phase canbe prepared by dissolving polyvinyl alcohol in deionized water. Thedeionized water can then be saturated with dichloromethane anddexamethasone acetate. The oil phase can be added to the water phasewith agitation with a high shear rotary immersion mixer to form anemulsion. The resulting oil-in-water emulsion can be further processedthrough a high shear microfluidizer to reduce the oil droplet size. Theresulting emulsion can be added to an excess of deionized water andcontinuously agitated to harden the polymeric microparticles. After 60minutes, the resulting microparticles can be isolated through 50 μm, 10μm, and 1 μm filters. The particles collected on the 1 micron filter canbe washed with deionized water, lyophilized, and then stored in sealedcontainers under refrigeration for further analysis. Sealed vials can begamma-irradiated prior to analysis or administration.

Injectable suspensions of Formulation [B] can be prepared in water(sterile water for injection) and in silicone oil. Particles areexpected to settle in less than 1 hour in water but to remain as astable suspension in silicone oil. The silicone oil is not expected todissolve the polymeric microparticles.

Intravitreal Injections in Rabbit

Anesthetized New Zealand Dutch Belted rabbits can be used in this study;topical antibiotic drops can be applied to the treated eyes, and 0.1 mLof Formula [B] can be injected via a 25 gauge needle into the vitreousbody in either an aqueous vehicle, [C-a] or silicone oil [C-s]. Prior totreatment, baseline fundus photos can be taken and an ophthalmicexamination can be performed. At scheduled times, animals can beeuthanized and the vitreous body of the treated eyes removed bydissection. The microparticles can be isolated from the vitreous fluid.Drug content of vitreous fluid and isolated microparticles can beassayed using techniques known in the art. In a second rabbitpopulation, whole eyes can be enucleated and frozen. Cryomicrotomesections can be taken of the frozen eyes to determine location and sizedomain of injection contents.

The microparticles from the [C-a] injection are expected to be dispersedin various regions of the vitreous after 7 days. In contrast, themicroparticles from the [C-s]formulation are expected to be foundlocalized at the site of injection for over 60 days.

All publications, patents, and patent applications are incorporatedherein by reference. While in the foregoing specification this inventionhas been described in relation to certain specific embodiments thereof,and many details have been set forth for purposes of illustration, itwill be apparent to those skilled in the art that the present inventionis susceptible to additional embodiments, and that certain of thedetails described herein may be varied considerably without departingfrom the basic principles of the present invention.

1. A method for the treatment of back pain, the method comprisinginjecting an injectable, flowable composition into the epidural space,the composition comprising: (a) microparticles comprising an activepharmaceutical ingredient and a polymer, wherein the surface of themicroparticles are hydrophilic; and (b) a hydrophilic, liquid carriervehicle; wherein the microparticles are substantially miscible todispersible in the liquid carrier vehicle.
 2. The method of claim 1,wherein the microparticles have a d₅₀ of about 2 μm to about 5 μm. 3.The method of claim 1, wherein the active pharmaceutical ingredientcomprises an anti-inflammatory agent.
 4. The method of claim 1, whereinthe active pharmaceutical ingredient comprises a synthetic,glucocorticoid steroid.
 5. The method of claim 1, wherein the activepharmaceutical ingredient comprises dexamethasone acetate, 9alpha-fluoro-11-beta, 17-alpha, 21-trihydroxy-16alpha-methylpregna-1,4-diene-3,20-dione 21-acetate


6. The method of claim 1, wherein the polymer comprises an amphiphilicblock copolymer.
 7. The method of claim 1, wherein the polymer is acopolymer of lactic acid and glycolic acid (PLGA).
 8. The method ofclaim 1, wherein the polymer comprises at least one of PLGA-block-PEGand PLGA.
 9. The method of claim 1, wherein the microparticle surfacecomprises a greater weight percentage of PEG than the microparticlecore.
 10. The method of claim 1, wherein the microparticles are at leastone of biodegradable, bioerodible, and biocompatible.
 11. The method ofclaim 1, wherein the active pharmaceutical ingredient is present in aweight of up to about 40% the weight of the polymer.
 12. The method ofclaim 1, wherein the active pharmaceutical ingredient is present in aweight of at least about 10% the weight of the polymer.
 13. The methodof claim 1, wherein the active pharmaceutical ingredient is present in aweight of about 20-30% the weight of the polymer.
 14. The method ofclaim 1, wherein the hydrophilic, liquid carrier vehicle comprises anaqueous liquid.
 15. The method of claim 1, wherein the injectable,flowable composition has a total volume of less than about 5 mL.
 16. Themethod of claim 1, wherein the administration is carried out no morethan once per about 12 weeks.
 17. The method of claim 1, wherein theback pain is lower back pain.
 18. The method of claim 1, wherein theback pain is chronic.
 19. The method of claim 1, wherein the back painis acute.
 20. A method for the treatment of back pain, the methodcomprising injecting no more than once per about 12 weeks an injectable,flowable composition having a total volume of less than about 5 mL intothe epidural space, the composition comprising: (a) microparticlescomprising dexamethasone acetate and a polymer, wherein the surface ofthe microparticles are hydrophilic, the microparticles have a d₅₀ ofabout 2 μm to about 5 μm, the polymer comprises a block copolymer oflactic acid and glycolic acid (PLGA) and polyethylene glycol (PEG), andthe active pharmaceutical ingredient is present in a weight of up toabout 40% the weight of the polymer; and (b) a hydrophilic, aqueousliquid carrier vehicle; wherein the microparticles are substantiallymiscible to dispersible in the liquid carrier vehicle.